PROJECT SUMMARY Hearing loss is one of the most prevalent sensory deficits that affect one in five individuals in the United States. While the underlying etiology can vary widely, viral infections are speculated to be associated with hearing loss with a sudden onset. Lassa fever (LF), caused by Lassa virus (LASV), is a major public health threat in West Africa and is characterized by acute hemorrhagic disease and/or neurological sequelae, and up to 500,000 cases are reported annually. Approximately 30% of LF survivors develop sudden onset hearing loss weeks or months after leaving the hospital, placing a huge burden on the public health system and impacting patients' quality of life. This phenomenon is quite unique because it typically develops at later stages of the disease process, thus making LF the only viral infection described in medical literature that induces hearing loss mostly in the convalescence phase. Until now, the lack of a robust animal model exhibiting sudden onset hearing loss induced by LASV prevented the mechanistic study of this clinical feature. To address this need, we developed a novel murine model for LF that mimics many symptoms of human LF. Most importantly, our model consistently reproduced the hearing loss in animals that were recovering from infection. This powerful tool will allow us, for the first time, to study the pathogenesis of hearing loss associated with LF, in a maximum containment BSL-4 setting. The long-term goal of our research is to identify the immunological and pathological mechanisms responsible for LASV-induced hearing loss in human patients to enable future treatment. The objective of this application is to use our physiologically relevant LF mouse model to study the mechanism of LF associated hearing loss, as well as to assess auditory damage of LF survivors in West Africa. Therefore, we propose the following Specific Aims: 1. Determine the mechanism of hearing loss in LASV-infected Stat1-/- mice. We will investigate the underlying mechanism by focusing on the inner ear, as well as determining the involvement of the central nervous system in hearing loss, by studying the auditory behavior of infected mice in order to define the localization of the injury and assess histopathological changes in the inner ear. 2. Identify the role of T cells in the development of hearing loss by performing loss/gain of function experiments. We will utilize T cell depletion and adoptive transfer techniques to determine the contribution of T cells to hearing loss in infected Stat1-/- mice. We will also identify the viral antigen most essential for T cell recruitment to the auditory nerve. 3. Determine the degree of hearing loss and location of functional damage in human patients exhibiting SHL after surviving LASV infection. We propose to investigate the underlying the hearing loss in documented LF survivors in Nigeria by using noninvasive diagnostic tests routinely performed during newborn hearing screening in the USA.